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Renata Risi Department of Experimental Medicine, Sapienza University of Rome, Sapienza University of Rome, Rome, Italy
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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Antonio Vidal-Puig University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, P. R. China
Centro de Investigacion Principe Felipe, Valencia, Spain

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Guillaume Bidault University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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Obesity and diabetes represent two increasing and invalidating public health issues that often coexist. It is acknowledged that fat mass excess predisposes to insulin resistance and type 2 diabetes mellitus (T2D), with the increasing incidence of the two diseases significantly associated. Moreover, emerging evidence suggests that obesity might also accelerate the appearance of type 1 diabetes (T1D), which is now a relatively frequent comorbidity in patients with obesity. It is a common clinical finding that not all patients with obesity will develop diabetes at the same level of adiposity, with gender, genetic, and ethnic factors playing an important role in defining the timing of diabetes appearance. The adipose tissue (AT) expandability hypothesis explains this paradigm, indicating that the individual capacity to appropriately store energy surplus in the form of fat within the AT determines and prevents the toxic deposition of lipids in other organs, such as the pancreas. Thus, we posit that when the maximal storing capacity of AT is exceeded, individuals will develop T2D. In this review, we provide insight into mechanisms by which the AT controls pancreas lipid content and homeostasis in case of obesity to offer an adipocentric perspective of pancreatic lipotoxicity in the pathogenesis of diabetes. Moreover, we suggest that improving AT function is a valid therapeutic approach to fighting obesity-associated complications including diabetes.

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Xiong Weng Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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Hao Jiang Gene Expression and Regulation, School of Life Sciences, University of Dundee, Dundee, Scotland, UK

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David J Walker Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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Houjiang Zhou MRC Protein Phosphorylation Unit, School of Life Sciences, Dundee, Scotland, UK

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De Lin Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee, Scotland, UK

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Jing Wang Science for Life Laboratory, Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden

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Li Kang Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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CD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type-specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressing Pparg expression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. These data were further supported by increased preadipocyte proliferation rates in CD44-deficient cells and re-expression of CD44 diminished this effect. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPARγ and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.

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Graham W Aberdeen Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

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Jeffery S Babischkin Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

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Gerald J Pepe Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia, USA

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Eugene D Albrecht Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

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We recently showed that the ratio of capillaries to myofibers in skeletal muscle, which accounts for 80% of insulin-directed glucose uptake and metabolism, was reduced in baboon fetuses in which estrogen was suppressed by maternal letrozole administration. Since vascular endothelial growth factor (VEGF) promotes angiogenesis, the present study determined the impact of estrogen deprivation on fetal skeletal muscle VEGF expression, capillary development, and long-term vascular and metabolic function in 4- to 8-year-old adult offspring. Maternal baboons were untreated or treated with letrozole or letrozole plus estradiol on days 100–164 of gestation (term = 184 days). Skeletal muscle VEGF protein expression was suppressed by 45% (P < 0.05) and correlated (P = 0.01) with a 47% reduction (P < 0.05) in the number of capillaries per myofiber area in fetuses of baboons in which serum estradiol levels were suppressed 95% (P < 0.01) by letrozole administration. The reduction in fetal skeletal muscle microvascularization was associated with a 52% decline (P = 0.02) in acetylcholine-induced brachial artery dilation and a 23% increase (P = 0.01) in mean arterial blood pressure in adult progeny of letrozole-treated baboons, which was restored to normal by letrozole plus estradiol. The present study indicates that estrogen upregulates skeletal muscle VEGF expression and systemic microvessel development within the fetus as an essential programming event critical for ontogenesis of systemic vascular function and insulin sensitivity/glucose homeostasis after birth in primate offspring.

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Elisa Villalobos E Villalobos, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Allende Miguelez-Crespo A Miguelez-Crespo, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Ruth A Morgan R Morgan, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Lisa Ivatt L Ivatt, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Mhairi Paul M Paul, The Queen's Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Joanna P Simpson J Simpson, The Queen's Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Natalie ZM Z.m. Homer N Homer, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Dominic Kurian D Kurian, The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, The University of Edinburgh The Roslin Institute, Roslin, United Kingdom of Great Britain and Northern Ireland

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Judit Aguilar J Aguilar, The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, The University of Edinburgh The Roslin Institute, Roslin, United Kingdom of Great Britain and Northern Ireland

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Rachel Kline R Kline, The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush, The University of Edinburgh The Roslin Institute, Roslin, United Kingdom of Great Britain and Northern Ireland

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T Wishart T Wishart, The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Easter Bush, The University of Edinburgh The Roslin Institute, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Nicholas Morton N Morton, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Roland H Stimson R Stimson, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Ruth Andrew R Andrew, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Brian R Walker B Walker, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Mark Nixon M Nixon, The Queen’s Medical Research Institute, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Glucocorticoids modulate glucose homeostasis, acting on metabolically active tissues such as liver, skeletal muscle, and adipose tissue. Intracellular regulation of glucocorticoid action in adipose tissue impacts metabolic responses to obesity. ATP-binding cassette family C member 1 (ABCC1) is a transmembrane glucocorticoid transporter known to limit the accumulation of exogenously administered corticosterone in adipose tissue. However, the role of ABCC1 in the regulation of endogenous glucocorticoid action and its impact on fuel metabolism has not been studied. Here, we investigate the impact of Abcc1 deficiency on glucocorticoid action and high fat-diet (HFD)-induced obesity. In lean mice, deficiency of Abcc1 increased endogenous corticosterone levels in skeletal muscle and adipose tissue but did not impact insulin sensitivity. In contrast, Abcc1-deficient mice on HFD displayed impaired glucose and insulin tolerance, and fasting hyperinsulinemia, without alterations in tissue corticosterone levels. Proteomics and bulk RNA sequencing revealed that Abcc1 deficiency amplified the transcriptional response to an obesogenic diet in adipose tissue but not in skeletal muscle. Moreover, Abcc1 deficiency impairs key signalling pathways related to glucose metabolism in both skeletal muscle and adipose tissue, in particular those related to OXPHOS machinery and Glut4. Together, our results highlight a role for ABCC1 in regulating glucose homeostasis, demonstrating diet-dependent effects that are not associated with altered tissue glucocorticoid concentrations.

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Ryan A. Lafferty R Lafferty, Life and Health Sciences, Ulster University, Coleraine, United Kingdom of Great Britain and Northern Ireland

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Peter R Flatt P Flatt, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom of Great Britain and Northern Ireland

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Victor A Gault V Gault, University of Ulster, School of Biomedical Sciences, County Londonderry, BT52 1SA, Ireland

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Nigel Irwin N Irwin, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom of Great Britain and Northern Ireland

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Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs. antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease.

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Kaitlyn A. Colglazier K Colglazier, Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, United States

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Noyonika Mukherjee N Mukherjee, Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States

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Christopher J. Contreras C Contreras, Medicine, Indiana University School of Medicine, Indianapolis, United States

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Andrew T Templin A Templin, Medicine and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States

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β-cell death contributes to β-cell loss and insulin insufficiency in type 1 diabetes (T1D), and this β-cell demise has been attributed to apoptosis and necrosis. Apoptosis has been viewed as the lone form of programmed β-cell death, and evidence indicates that β-cells also undergo necrosis, regarded as an unregulated or accidental form of cell demise. More recently, studies in non-islet cell types have identified and characterized novel forms of cell death that are biochemically and morphologically distinct from apoptosis and necrosis. Several of these mechanisms of cell death have been categorized as forms of regulated necrosis and linked to inflammation and disease pathogenesis. In this review, we revisit discoveries of β-cell death in humans with diabetes and describe studies characterizing β-cell apoptosis and necrosis. We explore literature on mechanisms of regulated necrosis including necroptosis, ferroptosis and pyroptosis, review emerging literature on the significance of these mechanisms in β-cells, and discuss experimental approaches to differentiate between various mechanisms of β-cell death. Our review of the literature leads us to conclude that more detailed experimental characterization of the mechanisms of β-cell death is warranted, along with studies to better understand the impact of various forms of β-cell demise on islet inflammation and β-cell autoimmunity in pathophysiologically relevant models. Such studies will provide insight into the mechanisms of β-cell loss in T1D and may shed light on new therapeutic approaches to protect β-cells in this disease.

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Emma Rose McGlone Department of Surgery and Cancer, Imperial College London, London, UK

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Stephen R Bloom Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Tricia M-M Tan Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Metabolic-associated steatotic liver disease (MASLD) is closely associated with obesity. MASLD affects over 1 billion adults globally but there are few treatment options available. Glucagon is a key metabolic regulator, and its actions include the reduction of liver fat through direct and indirect means. Chronic glucagon signalling deficiency is associated with hyperaminoacidaemia, hyperglucagonaemia and increased circulating levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF-21). Reduction in glucagon activity decreases hepatic amino acid and triglyceride catabolism; metabolic effects include improved glucose tolerance, increased plasma cholesterol and increased liver fat. Conversely, glucagon infusion in healthy volunteers leads to increased hepatic glucose output, decreased levels of plasma amino acids and increased urea production, decreased plasma cholesterol and increased energy expenditure. Patients with MASLD share many hormonal and metabolic characteristics with models of glucagon signalling deficiency, suggesting that they could be resistant to glucagon. Although there are few studies of the effects of glucagon infusion in patients with obesity and/or MASLD, there is some evidence that the expected effect of glucagon on amino acid catabolism may be attenuated. Taken together, this evidence supports the notion that glucagon resistance exists in patients with MASLD and may contribute to the pathogenesis of MASLD. Further studies are warranted to investigate the direct effects of glucagon on metabolism in patients with MASLD.

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Samrin Kagdi Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

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Sulayman A Lyons Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

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Jacqueline L Beaudry Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

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Adipose tissue was once known as a reservoir for energy storage but is now considered a crucial organ for hormone and energy flux with important effects on health and disease. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted from the small intestinal K cells, responsible for augmenting insulin release, and has gained attention for its independent and amicable effects with glucagon-like peptide 1 (GLP-1), another incretin hormone secreted from the small intestinal L cells. The GIP receptor (GIPR) is found in whole adipose tissue, whereas the GLP-1 receptor (GLP-1R) is not, and some studies suggest that GIPR action lowers body weight and plays a role in lipolysis, glucose/lipid uptake/disposal, adipose tissue blood flow, lipid oxidation, and free-fatty acid (FFA) re-esterification, which may or may not be influenced by other hormones such as insulin. This review summarizes the research on the effects of GIP in adipose tissue (distinct depots of white and brown) using cellular, rodent, and human models. In doing so, we explore the mechanisms of GIPR-based medications for treating metabolic disorders, such as type 2 diabetes and obesity, and how GIPR agonism and antagonism contribute to improvements in metabolic health outcomes, potentially through actions in adipose tissues.

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Affiong Ika Oqua Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Yusman Manchanda Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Emma Rose McGlone Department of Surgery and Cancer, Imperial College London, London, UK

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Ben Jones Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Sarah Rouse Department of Life Sciences, Imperial College, London, UK

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Alejandra Tomas Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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The glucagon receptor family are typical class B1 G protein-coupled receptors (GPCRs) with important roles in metabolism, including the control of pancreas, brain, and liver function. As proteins with seven transmembrane domains, GPCRs are intimately in contact with lipid bilayers and therefore can be putatively regulated by interactions with their lipidic components, including cholesterol, sphingolipids, and other lipid species. Additionally, these receptors, as well as the agonists they bind to, can undergo lipid modifications, which can influence their binding capacity and/or elicit modified or biased signalling profiles. While the effect of lipids, and in particular cholesterol, has been widely studied for other GPCR classes, information about their role in regulating the glucagon receptor family is only beginning to emerge. Here we summarise our current knowledge on the effects of cholesterol modulation of glucagon receptor family signalling and trafficking profiles, as well as existing evidence for specific lipid–receptor binding and indirect effects of lipids via lipid modification of cognate agonists. Finally, we discuss the different methodologies that can be employed to study lipid–receptor interactions and summarise the importance of this area of investigation to increase our understanding of the biology of this family of metabolically relevant receptors.

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Rebecca J Ainslie Institute for Regeneration and Repair, the University of Edinburgh, Edinburgh BioQuarter, Edinburgh, United Kingdom

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Ioannis Simitsidellis Institute for Regeneration and Repair, the University of Edinburgh, Edinburgh BioQuarter, Edinburgh, United Kingdom

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Phoebe M Kirkwood Institute for Regeneration and Repair, the University of Edinburgh, Edinburgh BioQuarter, Edinburgh, United Kingdom

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Douglas A Gibson Institute for Regeneration and Repair, the University of Edinburgh, Edinburgh BioQuarter, Edinburgh, United Kingdom

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Androgens can modulate immune cell function and may contribute to differences in the prevalence and severity of common inflammatory conditions. Although most immune cells are androgen targets, our understanding of how changes in androgen bioavailability can affect immune responses is incomplete. Androgens alter immune cell composition, phenotype, and activation by modulating the expression and secretion of inflammatory mediators or by altering the development and maturation of immune cell precursors. Androgens are generally associated with having suppressive effects on the immune system, but their impacts are cell and tissue context-dependent and can be highly nuanced even within immune cell subsets. In response to androgens, innate immune cells such as neutrophils, monocytes, and macrophages increase the production of the anti-inflammatory cytokine IL-10 and decrease nitric oxide production. Androgens promote the differentiation of T cell subsets and reduce the production of inflammatory mediators, such as IFNG, IL-4 and IL-5. Additionally, androgens/androgen receptor can promote the maturation of B cells. Thus, androgens can be considered as immunomodulatory agents, but further work is required to understand the precise molecular pathways that are regulated at the intersection between endocrine and inflammatory signals. This narrative review focusses on summarising our current understanding of how androgens can alter immune cell function and how this might affect inflammatory responses in health and disease.

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